Hepatitis C virus (HCV) infection is an important problem in individuals
who are also infected with HIV. HCV infection is very common in HIV-infected
individuals, occurring in approximately one quarter to one third of this
group, presumably as a consequence of shared routes of trans-mission related
to virologic and pathogenic aspects of the viral infections. Although
both are single-stranded RNA viruses and share similar epidemiologic properties,
there are many important differences. Although the quantity of HIV RNA
in plasma is an important prognostic determinant of HIV infection, this
has not been shown with HCV. A direct relationship is apparent between
HIV-related destruction of CD4 cells and the clinical consequences of
the disease resulting from immunodeficiency. The patho-genesis of HCV,
which occurs as a consequence of hepatic fibrosis, is much more complex.
The hepatic stellate cell, the major producer of the extracellular matrix
protein, is the main contributor to hepatic fibrosis, but the mechanism
by which HCV induces hepatic fibrosis remains unclear. Treatment of HCV
is increasingly important in HIV-infected patients due to improved HIV-associated
morbidity and mortality and due to the frequency with which HCV occurs
in patients with HIV-HCV coinfection. Timing of treatment initiation,
management of side effects, and possible effects of anti-HCV therapy on
HIV are among the issues that need consideration. Also, because several
issues concerning HCV are unique to coinfected patients, further research
is needed to determine optimal management of HCV in this setting.

Introduction

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are similar
in many respects. Both viruses have a single-stranded RNA genome, both
have very high levels of viral replication, both cause chronic infection,
and the two viruses share similar routes of transmission. However, HIV
and HCV are also different in many respects. Many of the differences in
the clinical manifestations, pathogenesis, and treatment of these viruses
can be attributed to differences in the target cell of each virus- the
hepatocyte for HCV and the CD4 + cell for HIV. >From an epidemiologic
standpoint, HCV is a leading cause of chronic hepatitis, cirrhosis, and
hepatocellular carcinoma. In the United States, HCV infection is the main
indication for liver transplantation. Recently, HIV-associated morbidity
and mortality have declined dramatically as a result of potent antiretroviral
therapy. Concomitantly, the incidence of liver disease is increasing in
HIV-infected individuals, a large proportion of which can be attributed
to HCV infection. The epidemiology, disease course, and management of
HCV are different in HIV-HCV coinfected individuals compared with HCV-monoinfected
individuals. This review focuses on current advances in HCV-HIV coinfection,
particularly in the area of HCV pathogenesis in coinfected patients. In
addition, we discuss the epidemiology, diagnosis, and treatment of HCV
in coinfected individuals.

Epidemiology

Approximately 3.8 million individuals in the United States (1.8% of the
population) have been exposed to HCV, and 2.7 million of these individuals
have detectable HCV RNA, indicating chronic viral infection [1]. Approximately
200 million individuals worldwide have been exposed to HCV [2]. The factors
most frequently implicated in HCV trans-mission are blood transfusion
before 1990 and intra-venous drug use, although in some cases no risk
factors can be found [1,3]. In comparison, about 30% of the 800,000 HIV-infected
individuals in the United States are coinfected with HCV as a consequence
of shared transmis-sion routes [4oo]. HIV-HCV coinfected individuals have
increased risk of sexual and maternal-fetal transmission of HCV virus
[5,6]. Maternal-fetal transmission is not common, having a reported prevalence
of 1.7% among HCV-monoinfected individuals; the rate of transmission is
increased to 19.4% among women coinfected with HIV [7]. Recent studies
suggest that, in the era of potent anti-retroviral therapy, the number
of deaths caused by liver disease in HIV-1-infected individuals has been
increasing. In a cohort of approximately 4000 individuals, liver disease
was the primary cause of non-AIDS death [8]. In a recently published study
that retrospectively examined the causes of death between 1991 and 1998
in HIV-1-seroposi-tive individuals, end-stage liver disease was found
to be the leading cause among those who were hospitalized [9]. The majority
of these individuals were HCV positive.

Pathogenesis of HCV

Hepatitis C virus, a member of the Flaviviridae family [10] based on its
genome sequence, has been classified into at least six genotypes and more
than 50 subtypes. Genotype 1 is the most common in the United States,
Europe, and Japan followed by genotypes 2 and 3. Genotype 4 is found in
the Middle East and in Central Africa. Genotype 5 is confined to South
Africa. Genotype 6 is distributed throughout Southeast Asia [11]. The
mechanisms responsi-ble for tissue injury in HCV infection are not well
under-stood. HCV cell targets are hepatocytes and possibly B lymphocytes
[12].

Mortality due to HCV results from progressive hepatic fibrosis that can
lead to cirrhosis and its complications. The clinical manifestations of
HIV infection are usually systemic, whereas those of HCV relate principally
to the liver. Because of the loss of CD4 + cell function, the primary
consequences of HIV infection result from immuno-deficiency. As a result
of HCV target cell localization in the liver, the infection is principally
concentrated in that organ. Its clinical manifestations, usually first
evident during late-stage disease, primarily result from the accu-mulation
of hepatic fibrosis and ultimately may culminate in hepatic dysfunction.

Significance of HIV and HCV RNA determinations

Chronic infection with both HIV and HCV is character-ized by dynamic equilibrium
between virus production and clearance. Studies of viral kinetics, in
which mathe-matical modeling is applied to the viral decay in response
to antiviral medications or after procedures such as plasma apheresis
that perturb the steady state, have been helpful in clarifying the viral
life cycle. Both HIV and HCV have very rapid life cycles, with an estimated
daily virion production of 9.3 log 10 to 10.2 log 10 for HIV and 11.6
log 10 to 13.0 log 10 for HCV, indicating that viral turnover is even
faster in HCV than it is in HIV infection [13]. The viral set point, the
quantity of HIV RNA in plasma 6 months after seroconversion, is an important
prognostic parameter in HIV infection. The set point indicates how likely
an individual is to progress to AIDS during the next 5 years [14]. During
primary HIV infection the HIV RNA level increases rapidly as virion production
greatly out-paces virion clearance. During the first 6 months after seroconversion,
the immune system is able to gain partial control over viral replication,
and the level of HIV RNA in plasma is decreased. During the asymptomatic
phase of the infection, a steady state is achieved in which virion production
equals virion clearance, presumably by the immune system. However, a progressive
destruction of CD4 + cells eventually results in profound immuno-deficiency.
Without effective treatment, most individuals become symptomatic during
late-stage disease as a conse-quence of various opportunistic infections.
The symptoms present during late-stage disease usually result from immunodeficiency,
which allows opportunistic infections to be established.

The relationship between the quantity of HCV RNA in serum, the pathogenesis
of the disease, and the develop-ment of clinical symptoms is not as straightforward
in HCV infection. The hepatic stellate cell (HSC) is the main fibrogenic
cell type in the liver, and it is the principal culprit in the pathogenesis
of HCV [15]. Many different stimuli can lead to HSC activation, most notably
inflam-mation in the liver. The hepatic inflammatory infiltrate within
the liver can lead to secretion of transforming growth factor-o (TGF-o
), which can lead to HSC activation and secretion of extracellular matrix
(ECM) protein [16]. Although a direct correlation between the quantity
of HCV RNA in serum and HCV pathogenesis has not been made, the quantity
of HCV RNA is one of the five determi-nants of an increased likelihood
of a successful outcome to antiviral therapy [17].

Significance of immune response against each virus

We have learned much about the importance of the immune response against
HIV. Although the hope of viral eradication was harbored by many researchers
and practi-tioners shortly after the development of the HIV protease inhibitors,
time has demonstrated that our efforts at HIV eradication have been thwarted
thus far. However, it does appear that early initiation of antiretroviral
therapy, prior to seroconversion, may alter the course of HIV as a result
of the retention of potent HIV-specific cellular immune responses that
may delay disease progression. Novel approaches to the treatment of HIV
involve boosting the immune response through a variety of mechanisms to
achieve immune-mediated virus suppression in the absence of therapy. This
approach has been demonstrated through "structured treatment interruptions"
that have recently become popular.

The immune response plays an important role in HCV pathogenesis [18].
A broad and strong anti-HCV-specific CD4 + immune response is an important
determinant of recovery during the acute phase of HCV [19,20] and in the
prevention of severe HCV recurrence after hepatic transplantation [21].
Vigorous HCV-specific CD8 immu-nity further distinguishes individuals
with self-limited HCV infection from individuals with chronic HCV infec-tion
[22,23]. Even in patients with chronic HCV infection, a strong HCV-specific
CD4 response may help protect these individuals against progressive liver
disease [20]. Moreover, both CD4 + and CD8 + responses to HCV structural
proteins (core, E1, and E2) are important deter-minants of a successful
outcome to therapy. Through the destruction of CD4 + cells with reactivity
for HCV, HIV may have a deleterious effect on immune responses in coinfected
patients, which may be one of the reasons why higher CD4 + T-cell counts
and lower HCV viremia have been associated with improved responsiveness
to interferon (IFN) [24-26]. Because IFN may also result in a dose-dependent
decrease in CD4 + T cells, it is impor-tant to initiate treatment as early
in the course of HIV infection as possible prior to the onset of severe
immuno-deficiency [27,28].

The central pathogenic mechanisms, whether direct viral cytotoxicity or
the immune response of the host, have not been conclusively established
for either virus, although each mechanism has been hypothesized to be
important in each viral infection. Recent reports have demonstrated that
the rate of hepatic fibrosis is accelerated in HIV-HCV coinfected individuals
[29oo,30o,31,32o]. Several studies have evaluated the determinants of
hepatic fibrosis in HCV-monoinfected and HIV-HCV coinfected individuals.
In HCV infection, age over 50 years, consumption of 50 g or more of alcohol
per day, and male gender are indepen-dently associated with accelerated
hepatic fibrosis [33,34]. In HIV-HCV coinfected individuals, HIV infection,
alcohol consumption of more than 50 g/d, CD4 cell count less than 200
cells/µL, and age over 25 years at the time of HCV acquisition are
all associated with accelerated hepatic fibrosis [29]. Puoti et al. [32]
found an independent associ-ation between CD4 + cell count less than 500
cells/mm 3 and increased rate of fibrous septa formation. A recent study
found that chronic use of antiretroviral therapy containing at least one
protease inhibitor, younger age at the time of HCV infection, low alcohol
intake, and high CD4 count were associated with a reduced hepatic fibrosis
progression rate in HCV-HCV coinfected individuals [35].

The pathogenic mechanisms by which increased hepatic fibrosis in HIV-HCV
coinfected individuals occurs have yet to be determined conclusively.
However, immuno-logic differences in HIV-HCV coinfected and HCV-monoinfected
individuals may account for the different rate of hepatic fibrosis, because
the inflammatory response has been shown to be an important determinant
of fibrosis in humans [34]. In preliminary evaluation we showed that the
number of proliferative and apoptotic liver cells were increased in HCV-monoinfected
and HCV-HIV coinfected individuals, compared with uninfected individuals
[36]. Upon further study, we found that CD4 + cells are signifi-cantly
decreased and that periportal hepatocyte prolifera-tion is increased in
HIV-HCV coinfected individuals, compared with HCV-monoinfected individuals
[37]. Deficient cytolytic activity and ineffective CD4 priming of CD8
responses may lead to dysfunctional CD8 + cells in HIV infection that
are deficient in cytolytic activity, impairing their ability to clear
infected hepatocytes, but retaining their ability to secrete cytokines
[38,39]. These cytokines may lead to hepatocyte injury, resulting in phagocytosis
by Kupffer cells, activation of hepatic stellate cells, and deposition
of hepatic fibrosis (Fig. 1). Our findings suggest that the resulting
hepatocyte injury may also stimulate de novo hepatocyte proliferation.
In HCV, dysfunctional peripheral blood CD8 + T cells are also characterized
by impaired cytolytic activity. In contrast to the situation in HIV, antiviral
cytokine secretion is diminished in these cells [40]. However, the existence
of dysfunctional intra-hepatic CD8 + cells in HCV remains to be evaluated.
Finally, a dependence of fibrosis on T-helper 2 responses, which are disproportionately
preserved in HIV patients, has been documented in IFN-o -deficient knockout
mice [41] and in schistosomiasis [42].

Clinical Manifestations

Most HIV- and HCV-infected individuals do not develop symptoms until late
in the course of their disease. During the initial stages of HIV infection,
patients usually present with symptoms similar to those in infectious
mononucleosis, including fever, lymphadenopathy, myalgias, arthal-gias,
and sweating [43]. The clinical consequences of the infection result directly
from immunodeficiency. The symptoms in acute HCV infection are typically
those seen with other forms of hepatitis: jaundice, scleral icterus, fatigue,
and weakness. However, the occurrence of acute symptoms may indicate important
differences in disease pathogenesis. For example, whereas the acute seroconver-sion
syndrome occurs in the majority of HIV-infected individuals, some have
suggested that the presence of symptoms during the acute phase of HCV
infection is associated with an increased likelihood of viral clearance
[44]. The symptoms that usually occur in late-stage HCV infection (ascites,
encephalopathy, prolonged prothrom-bin time, elevated bilirubin, and decreased
serum albumin) comprise the Child-Pugh scoring system, the most frequently
used measure to assess damage in end-stage liver disease.

HCV diagnosis in HIV-HCV coinfected individuals

With the realization that HCV is a frequent pathogen in HIV-infected individuals,
the United States Public Health Service and the Infectious Disease Society
of America issued guidelines in 1999 stating that all HIV-infected individuals
must be screened for anti-HCV antibodies [45]. With respect to these recommendations,
the concern has been raised regarding the most appropriate screening test,
whether measurement of anti-HCV antibodies, as determined by enzyme-linked
immunosorbent assay (ELISA), or HCV RNA, as determined by polymerase chain
reaction (PCR). Initially the concern was expressed that HIV-associated
immunodeficiency might result in false negative ELISA results. However,
recent investigations have shown that the predictive value of the anti-HCV
ELISA is significantly better in HIV-HCV coinfected individuals than it
is in HCV-monoinfected individuals [46]. The third-generation ELISA should
be performed to screen for HCV in HIV-HCV coinfected individuals [47].

In HIV-infected individuals, quantitation of the amount of HIV-1 RNA in
plasma is both an important predictor of disease progression and a measurement
of the efficacy of antiretroviral therapy. Additionally, the peripheral
blood CD4 + T-cell count provides important information concerning the
severity of the disease and the likelihood of a successful therapeutic
outcome [48]. In HCV, the amount of hepatic fibrosis, as opposed to the
level of HCV RNA, is the most important prognostic factor. However, quantita-tion
of serum HCV RNA and determination of the HCV genotype are important predictors
of the likelihood of therapeutic efficacy. Liver biopsy is the most specific
test for diagnosis and the assessment of hepatic pathology [49], and currently,
it is the only method by which to quantify the amount of hepatic fibrosis.
The biopsy is graded on the amount of inflammation and on the stage of
fibrosis on a 0-to-4 scale [50-52]. Most hepatologists recommend a liver
biopsy for histo-logic assessment of the liver, regardless of aminotransferase
or HCV RNA levels, because there is a poor correlation between the aminotransferase
level and the hepatic histo-logic features that may result from HCV. For
example, a subgroup of HCV-infected individuals have normal aminotransferase
levels despite clinically significant fibrosis or cirrhosis [53]. To arrest
disease progression, we believe that treatment should be more aggressively
pursued in patients with stage 2 or stage 3 fibrosis in the liver. Therapeutic
options At least 15 antiretroviral medications directed against specific
portions of HIV have been approved by the US Food and Drug Administration
(FDA). In contrast, agents used to treat HCV-IFN, IFN modified with polyethylene
glycol (PEG), and RBV-are nonspecific viral agents. The precise mechanisms
of action of IFN and RBV have not been discerned, but they appear to involve
both antiviral and immunomodulatory effects, and both effects appear to
be important in achieving therapeutic success. In HCV, several indicators
can be used to assess the degree of disease severity and therapeutic efficacy.
These include biochemical measurements (serum quantitation of alanine
aminotrans-ferase), virologic measurements (HCV RNA), and histologic measurements
(degree of fibrosis and inflammation on liver biopsy). Because clinical
symptoms do not usually present in chronic HCV infection until the development
of end-stage liver disease, symptomatic improvement cannot be used as
a means to assess therapeutic efficacy. The timing of a therapeutic response
is also important, ie, whether the response occurs at the end of the treatment
period (ETR) or 6 months after treatment is discontinued, with the latter
instance referred to as sustained virologic response (SVR). Because HCV
does not have a nuclear phase during its replication cycle and does not
integrate into the host genome as HIV does, HCV eradication may be a realistic
therapeutic target. Long-term follow-up studies have suggested that individuals
who achieve an SVR are very unlikely to have HCV recurrence [54,55]. Combination
therapy with IFN and RBV has been the standard treatment for HCV [56].
IFN can decrease the level of HIV, and it may prolong survival in HIV-mono-infected
individuals [57]. However, IFN attenuates the CD4 + cell response to HIV
when it is combined with nucleoside analogues [58]. Investigators in a
French prospective study reported that the response to IFN in chronic
HCV infection was not statistically different in HCV-monoinfected individuals,
compared with HIV-HCV coinfected individuals [59].

The efficacy of IFN and RBV in HIV-HCV coinfected individuals has been
documented in four published studies, including a total of 109 individuals
(Table 1) [60,61o,62,63]. All of these studies were conducted in Europe.
Three of the studies included primarily HCV-therapy nave individuals.
In three of the studies, intra-venous drug use was the primary risk factor
for HCV disease. The vast majority of study participants had between 300
and 500 CD4 lymphocytes/mm 3 and were on antiretroviral therapy. All study
participants received combination therapy with IFN and RBV for 6 to 12
months and achieved an SVR of 11% to 40%.

Recently IFN has been conjugated to polyethylene glycol (PEG), allowing
weekly dosing and bringing more sustained IFN levels [64]. Additional
improvements in the sustained virologic response may occur as a result
of basing the IFN and RBV doses on the body weight of the individual [65].
Studies of the efficacy of PEGylated IFN (PEG-IFN) and RBV in HIV-HCV
coinfection are currently in progress.

Side effects of treatment

Because of the relatively increased frequency of side effects with PEG-IFN
and RBV, the ability to tolerate these medica-tions is another issue that
warrants careful consideration in HIV-HCV coinfection. RBV is a guanoside
nucleoside analogue with antiviral activity against a variety of RNA and
DNA viruses, not including HIV [61]. In vitro RBV can phos-phorylate the
HIV reverse transcriptase inhibitors, particu-larly zidovudine and stavudine
(D4T), which could result in vivo in increased plasma HIV RNA [62,63].
However, in studies to date, significantly increased HIV RNA levels have
not been a major problem in RBV-treated individuals who were also treated
with HIV reverse transcriptase inhibitors. Anemia and neutropenia, both
of which are common side effects in HCV-infected patients who are prescribed
IFN and RBV, may be particularly problematic in HIV-HCV coinfected patients.
RBV can cause hemolytic anemia, and IFN can cause bone marrow suppression
resulting primarily in neutropenia but also in anemia. Anemia, which is
more prevalent in HIV-infected individuals compared with the general population,
is usually multi-factorial in HIV infection. Multiple antiretroviral medica-tions,
including nucleoside analogues that are associated with bone marrow suppression
and HIV infection itself, can contribute to anemia in these individuals.
The use of growth factors, granulocyte colony stimulating factor or erythropoietin,
may be beneficial in treating these side effects, particularly in HIV-HCV
coinfected patients.

Duration of therapy

In the treatment of HCV, the optimal duration of therapy has become an
important issue. Five independent charac-teristics have been associated
with a sustained virologic response: genotype 2 or 3, baseline viral load
less than 3.5 million copies/mL, no or minimal portal fibrosis, female
gender, and age less than 40 years [17]. Recently, Poynard et al. [64]
suggested that all HCV-infected individuals be treated for 24 weeks, at
which time HCV RNA should be determined by PCR. If HCV RNA is detectable,
treatment can be stopped. If PCR is negative and the patient has fewer
than four favorable factors, treatment should be continued for an additional
24 weeks. Whether the same factors also predict an increased likelihood
of a successful therapeutic response is yet to be determined, as is the
optimal duration of HCV treatment in HIV infection.

Conclusions

Several studies in HCV-monoinfected individuals have suggested that an
immune response directed against HCV is important to achieve a successful
response to therapy. It has also been suggested that a higher CD4 + cell
count is associated with improved outcome in the treatment of HCV in HIV-HCV
coinfected individuals. Early initiation of anti-HCV therapy, prior to
decrease of CD4 + T cells, may improve the efficacy of anti-HCV therapy
in HIV- HCV coinfection. Furthermore, delaying HCV therapy may necessitate
treatment of HIV and HCV simulta-neously with multiple medications, some
of which may have hepatotoxic effects. Therefore, we believe that therapy
for HCV should be initiated as early as possible in the course of HIV
disease. Additionally, initiation of anti-HCV therapy early in the course
of HIV may decrease if not halt the progression to cirrhosis. In individuals
with severe immunodeficiency, initiation of antiretroviral therapy before
anti-HCV therapy should be considered to improve patients' immune status
and decrease HIV replication. Clearly, further investigation is necessary
for a more accurate definition of the timing of treatment of HCV in HIV-HCV
coinfected individuals. In addition, further studies are needed to evaluate
the possible mecha-nisms by which antiretroviral therapy may prevent hepatic
fibrosis. Given the clinical and epidemiologic importance of HCV in HIV-infected
individuals, addi-tional research is necessary to more fully discern the
ways in which HCV pathogenesis and immune responses are altered in the
setting of HIV.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted
as:

61.o Zylberberg H, Benhamou Y, Lagneaux JL, et al.: Safety and efficacy
of interferon-ribavirin combination therapy in HCV-HIV coinfected subjects:
an early report. Gut 2000, 47:694-697. This trial evaluated the safety
and efficacy of combination therapy using interferon and ribavirin in
HIV-HCV coinfected individuals who were nonresponders or relapsers after
treatment with standard interferon. The sustained virologic response rate
in these patients was 14.3%.